Gap junction channels provide pathways of intercellular communication=, allowing the passage of ions and small molecules up to 1 kDa in mass or 10-14 nm in diameter. In mammalian and other vertebrate cells, gap junction channels are composed of a family of protein molecules known as connexins. Determination of the roles of channels formed by various connexins is an ongoing area of investigation. One problem with studying gap junction channels is the lack of blockers that are specific and selective. The lack of naturally occurring blockers has in part been attributed to the inaccessibility of gap junctions to extracellular space and the large pore size of these channels. We recently discovered that quinine, a small naturally occurring compound, has significant effects on gap junction channels formed of certain connexins at concentrations comparable to its effect on other cellular processes. The experiments proposed in this project will enable us to understand the mechanism of action of quinine and molecular basis for its action on gap junction channels. These studies combined with future structure-activity studies may lead to the identification or synthesis of a blocking agent that is highly specific for gap junction channels.